# B cells in autoimmunity following checkpoint blockade therapy

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $465,726

## Abstract

PROJECT SUMMARY
Combination checkpoint blockade (CCB) therapy with anti-CTLA4 and anti-PD1 antibodies leads to high rates
of tumor regression and has been approved by the FDA for upfront treatment of patients with advanced
melanoma and is currently being evaluated in other tumors. Unfortunately, CCB also leads to high rates of
immune-related adverse events (IRAEs), with over half of the treated patients experiencing grade 3-4 IRAEs
leading to discontinuation of therapy in over a third of patients. Hence, development of IRAEs remain a major
obstacle to optimal application of combination checkpoint blockade in human cancer. From a practical
perspective, it would be highly desirable if patients at increased risk for the development of autoimmunity could
be identified before clinical toxicity and the risk of autoimmunity reduced by preemptive intervention, without
affecting clinical efficacy. This application builds on our recent studies to evaluate treatment-induced changes in
immune cells that correlate with the risk of development of IRAEs. In these studies, we have observed that CCB
therapy leads to a distinct pattern of changes in B cells which preceded and correlated with both the frequency
and timing of IRAEs. In contrast, treatment-induced proliferation in circulating CD4 or CD8 T cells or quantitative
changes in other immune cells (NK cells, monocytes) did not correlate with or predict the development of IRAEs.
We hypothesize that patients with early changes in B cells identify a cohort at high risk for the development of
autoimmunity following CCB. Preclinical models have to date not recapitulated the spectrum of CCB-associated
autoimmunity observed in the clinic, supporting the need for human studies. The specific aims are:
Aim 1. To validate B cell changes as a biomarker for increased risk of IRAEs in melanoma patients receiving
CCB therapy and to evaluate the long term effects of CCB therapy on B cell subsets and function compared to
those observed in the context of naturally occurring autoimmunity.
Aim 2. To identify antigenic targets of B cells expanded following CCB therapy and examine their ability to
serve as antigen presenting cells.
Aim 3. To examine the role of T helper subsets cells in the activation of CD21lo B cells in patients receiving
CCB therapy.
We hope these studies will provide a simple marker for identifying increased risk for autoimmunity following
combination checkpoint therapy. Understanding B cell changes, defining their antigenic targets and the role of T
cells in inducing these B cell changes may also help to identify new pathways and targets for prevention and
treatment of IRAEs following combination checkpoint blockade therapy.

## Key facts

- **NIH application ID:** 9893845
- **Project number:** 5R01CA238471-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Kavita Madhav Dhodapkar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $465,726
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893845

## Citation

> US National Institutes of Health, RePORTER application 9893845, B cells in autoimmunity following checkpoint blockade therapy (5R01CA238471-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9893845. Licensed CC0.

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